Crystalline forms of atorvastatin

ABSTRACT

The present invention is directed to new crystalline forms of Atorvastatin calcium (2:1), referred to hereinafter as polymorphic Forms X, A, B1, B2, C, D and E. Furthermore, the present invention is directed to processes for the preparation of these crystalline forms and pharmaceutical compositions comprising the crystalline forms.

[0001] The present invention is directed to crystalline forms ofAtorvastatin calcium, processes for their preparation and pharmaceuticalcompositions comprising these crystalline forms.

[0002] The present invention relates to crystalline forms ofAtorvastatin calcium. Atorvastatin calcium is known by the chemicalname,[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1). Atorvastatin has the following formula:

[0003] Atorvastatin calcium is an orally-active hypocholesterolaemic, aliver-selective HMG-CoA reductase inhibitor. Processes for thepreparation of Atorvastatin calcium are described in U.S. Pat. No.5,298,627, U.S. Pat. No. 5,273,995 and WO-A-97/03960, and publicationsby P. L. Brower et al. in Tetrahedron Letters (1992), vol. 33, pages2279-2282, K. L. Baumann et al. in Tetrahedron Letters (1992), vol. 33,pages 2283-2284 and A. Graul et al. in Drugs Future (1997), vol. 22,pages 956-968.

[0004] This calcium salt (2:1) is desirable since it enablesAtorvastatin calcium to be conveniently formulated. The processes in theabove mentioned patents and publications result in the preparation ofamorphous Atorvastatin calcium.

[0005] The preparations of Atorvastatin calcium (2:1) described inWO-A-97/03958 and WO-A-97/03959 result in the isolation of crystallineAtorvastatin calcium with the polymorphic forms III, and I, II, and IV,respectively. However, there is still a need to produce Atorvastatincalcium in a reproducible, pure and crystalline form to enableformulations to meet exacting pharmaceutical requirements andspecifications. Furthermore, it is economically desirable that theproduct is stable for extended periods of time without the need forspecialised storage conditions.

[0006] Surprisingly, there have now been found several novel crystallineforms of Atorvastatin calcium salt (2:1), herein designated as Form X,Form A, Form B1, Form B2, Form C, Form D and Form E. The novel forms ofthe present invention have a good thermal stability and/or goodsolubility characterisitics.

[0007] Accordingly, the present invention is directed to the followingpolymorphic Forms X, A, B1, B2, C, D and E of Atorvastatin calcium salt(2:1).

[0008] A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at

27.9 (s), 20.9 (w), 18.9 (w), 16.1 (w), 11.1 (m), 10.5 (m), 9.1 (m),5.53 (m), 5.07 (w), 4.77 (vw), 4.55 (m), 4.13 (w), 3.69 (w);

[0009] herein designated as Form X. Here and in the following theabbreviations in brackets mean: (vs)=very strong intensity; (s)=strongintensity; (m)=medium intensity; (w)=weak intensity; (vw)=very weakintensity.

[0010] A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at

31.0 (vw), 18.6 (m), 17.0 (w), 15.3 (vw), 12.8 (w), 11.2 (m), 9.6 (s),9.3 (w), 8.6 (w), 7.4 (m), 6.5 (vw), 6.2 (vw), 5.47 (w), 5.21 (m), 4.64(vs), 4.46 (s), 4.14 (m), 3.97 (m), 3.74 (m), 3.62 (vw), 3.38 (w), 3.10(m),

[0011] herein designated as Form A.

[0012] A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at

27.9 (m), 17.0 (m), 14.2 (w), 12.1 (vs), 10.1 (s), 8.6 (m), 7.1 (m), 6.1(vw), 5.27 (m), 4.89 (m), 4.68 (m), 4.46 (m), 4.22 (m), 3.90 (w), 3.70(w), 2.36 (vw),

[0013] herein designated as Form B1.

[0014] A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at

28.1 (m), 17.2 (m), 14.0 (vw), 12.3 (s), 10.4 (s), 8.6 (m), 7.5 (w), 7.0(m), 5.28 (m), 4.88 (m), 4.55 (m), 4.27 (m), 3.88 (vw), 3.73 (m),

[0015] herein designated as Form B2.

[0016] A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at

[0017] 28.8 (m), 24.0 (m), 17.1 (m), 11.3 (s), 9.8 (vw), 8.3 (w), 7.7(vw), 6.9 (vw), 5.64 (vw), 5.21 (w), 4.59 (m), 4.39 (w), 4.16 (w), 3.70(w),

[0018] herein designated as Form C.

[0019] A crystalline polymorph of[R-(R*,R*)]-2-(4fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at

33.7 (w), 31.0 (m), 16.9 (m), 10.3 (s), 7.7 (w), 6.4 (vw), 4.84 (s),

[0020] herein designated as Form D.

[0021] A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at

26.8 (s), 9.4 (w), 4.6 (m)

[0022] herein designated as Form E.

[0023] A discussion of the theory of X-ray powder diffraction patternscan be found in “X-ray diffraction procedures” by H. P. Klug and L. E.Alexander, J. Wiley, New York (1974).

[0024] Furthermore, the present invention is directed to processes forthe preparation of Form X, Form A, Form B1, Form B2, Form C, Form D andForm E.

[0025] Form X can generally be prepared by drying of a solution ofAtorvastatin calcium in an organic solvent. Examples of such organicsolvents are alcohols, like methanol. Preferably, the solution inaddition contains an organic non-solvent, like ethers, for examplemethyl tert.-butyl ether. Drying can be carried out at elevatedtemperature, or, preferably, at ambient temperature. If desired, duringthe preparation process seeding with Form X can be carried out.

[0026] Form A can generally be prepared by suspending Form X or theamorphous form in an organic solvent, like an alcohol, especiallyisopropanol. It is preferred that the organic solvent contains as afurther solvent some water. The amount of water is preferably about 0.1to 5%, preferably about 0.5 to 2%, especially about 1% by volume of thesuspension. It is preferred that the suspension is treated attemperatures between 10 and 60° C. (preferably 30 to 50° C.), especiallyfor a longer period of time, like 10 to 40 hours. If desired, during thepreparation process seeding with Form A can be carried out. Form A canalso be prepared from Atorvastatin lacton upon subsequent reaction withNaOH to form Atorvastatin sodium followed by reaction with CaCl₂ in anorganic solvent, like an alcohol, especially isopropanol. It is preferedthat the organic solvent contains as a further solvent some water. Theamount of water is preferably 0.1 to 10%. If desired, during thepreparation process seeding with Form A can be carried out. Form A canalso be prepared directly from Atorvastatin lactone upon reaction withCa(OH)₂ in an organic solvent, like an alcohol, especially isopropanol.It is prefered that the organic solvent contains as a further solventsome water. The amount of water is preferably 0.1 to 10%. If desired,during the preparation process seeding with Form A can be carried out.

[0027] Form A can also be prepared by the reaction of Atorvastatinammonium salt with Ca(II)-acetate in an organic solvent or a mixture oforganic solvents, preferably a mixture of tert-butyl methyl ether (TBME)and isopropanol. The solid formed in this reaction is isolated byfiltration and than stirred as a suspension in an organic solvent, likean alcohol, especially isopropanol. It is prefered that the organicsolvent contains as a further solvent some water. The amount of water ispreferably 0.1 to 10%. It is prefered that the suspension is treated attemperatures between 10 and 60° C., especially for a longer period oftime, like 10 to 60 hours. If desired, during the preparation processseeding with Form A can be carried out.

[0028] Form B1 can generally be prepared by suspending Form X or theamorphous form in acetonitrile containing a further organic solvent,like tetrahydrofuran. It is prefered that the suspension is treated attemperatures between 10 and 50° C. (preferably ambient temperature),especially for a longer period of time, like 10 to 40 hours. If desired,during the preparation process seeding with Form B1 can be carried out.

[0029] Form B2 can generally be prepared by suspending Form X or theamorphous form in acetonitrile, preferably pure acetonitrile. It ispreferred that the suspension is treated at temperatures between 10 and50° C. (preferably 30 to 50° C.), especially for a longer period oftime, like 10 to 40 hours. If desired, during the preparation processseeding with Form B2 can be carried out.

[0030] Form C can generally be prepared by suspending Form X or theamorphous form in a mixture of isopropanol and water, and treating thesuspension at ambient temperature for a longer period of time, like 10to 40 hours. If desired, during the preparation process seeding withForm C can be carried out.

[0031] Form D can generally be prepared by suspending Form X or theamorphous form in a mixture of ethanol and water at temperatures betweenabout 20 to 60° C. for a longer period of time, like 10 to 40 hours. Ifdesired, during the preparation process seeding with Form D can becarried out.

[0032] Form E can generally be prepared by evaporation of a solution ofany form of Atorvastatin, preferably Form X, in 2-butanone or fromsolvent mixtures of 2-butanone with heptane or ethylacetate or ternarymixtures of 2-butanone, heptane and ethylacetate. Evaporation ispreferably carried out slowly, for example within 10 to 40 hours.

[0033] Another object of the present invention are pharmaceuticalcompositions comprising an effective amount of crystalline polymorphicForm X, Form A, Form B1, Form B2, Form C, Form D or Form E, and apharmaceutically acceptable carrier.

[0034] The polymorphic forms may be used as single components ormixtures.

[0035] As to the novel polymorphic forms of Atorvastatin calcium it ispreferred that these contain 25-100% by weight, especially 50-100% byweight, of at least one of the novel forms, based on the total amount ofAtorvastatin calcium. Preferably, such an amount of the novelpolymorphic forms of Atorvastatin calcium is 75-100% by weight,especially 90-100% by weight. Highly preferred is an amount of 95-100%by weight.

[0036] The following Examples illustrate the invention in more detail.Temperatures are given in degrees Celsius.

EXAMPLE 1 Preparation of Polymorphic Form X

[0037] Atorvastatin calcium Form X is prepared by dissolving 127 mgAtorvastatin calcium in a mixture of 2.0 ml methanol and 6.0 ml methyltert.-butyl ether and drying of the solution at ambient temperature.Form X is characterized by a x-ray powder diffraction pattern as shownin FIG. 1. Differential scanning calorimetry in a closed sample pansealed after equilibrium under dry nitrogen for about 16 hours atambient temperature shows a melting point of 168° C. and an enthalpy offusion of about 27 J/g (see FIG. 6). Form X if stored under normalconditions contains about 4% of water.

EXAMPLE 2 Preparation of Polymorphic Form A

[0038] Form A is prepared by suspending 100 mg of Form X in 3.0 mlisopropanol together with 50 μl H₂O and stirring of this suspension at40° C. After 9 hours an additional amount of 50 μl of water is added tothe suspension and stirring is continued at 40° C. for another 20 hours.The suspension is filtrated and crystalline Form A is obtained. Form Ais characterized by a x-ray powder diffraction pattern as shown in FIG.2. Differential scanning calorimetry of Form A in a closed sample pansealed after equilibration under dry nitrogen for about 16 hours atambient temperature reveals a melting point of 179° C. and an enthalpyof fusion of 53 J/g (see FIG. 6).

[0039] In the above example it is also possible to start from theamorphous form of Atorvastatin calcium instead of Form X.

EXAMPLE 3 Preparation of Polymorphic Form B1

[0040] Atorvastatin calcium crystal Form B1 is prepared by suspending145 mg of Atorvastatin calcium Form X in a mixture of 1.0 mlacetonitrile and 1.0 ml of tetrahydrofuran at ambient temperature. Whilethe cap of the reaction vial is left open some of the tetrahydrofuranevaporates which leads to a slow reduction of the solubility ofAtorvastatin calcium in the system. After 3.5 hours an additional amountof 1.0 ml of acetonitrile is added to the reaction container andstirring is continued for about 15 hours at ambient temperature. Afterfiltration of the suspension crystal form B1 is obtained. Form B1 ischaracterized by a x-ray powder diffraction pattern as shown in FIG. 3.

[0041] In the above example it is also possible to start from theamorphous form of Atorvastatin calcium instead of Form X.

EXAMPLE 4 Preparation of Polymorphic Form B2

[0042] Form B2 is prepared by suspending 117 mg of Atorvastatin calciumForm X in 2.0 ml of acetonitrile and stirring this suspension at 40° C.for about 18 hours. In order to reduce the viscosity of the suspension1.0 ml of acetonitrile is added at ambient temperature to thissuspension after the end of the crystallization process. The obtainedproduct is crystal Form B2 which is characterized by an x-ray powderdiffraction pattern as shown in FIG. 3.

[0043] In the above example it is also possible to start from theamorphous form of Atorvastatin calcium instead of Form X.

EXAMPLE 5 Preparation of Polymorphic Form C

[0044] Form C is prepared by suspending 120 mg of Atorvastatin calciumForm X in a mixture of 3.0 ml isopropanol and 1.0 ml water. After onehour of stirring at ambient temperature 2.0 ml water are added andstirring is continued for 15 hours at the same temperature. Afterfiltration of the suspension crystal Form C is obtained which ischaracterized by the x-ray diffraction pattern as shown in FIG. 4.

[0045] In the above example it is also possible to start from theamorphous form of Atorvastatin calcium instead of Form X.

EXAMPLE 6 Preparation of Polymorphic Form D

[0046] Form D is prepared by suspending 124 mg of Form X in 3.0 ml ofethanol and by stirring this suspension at ambient temperature. Afterabout 2 hours a suspension of high viscosity is obtained and 1.0 ml ofwater are added to the suspension, which reduces the viscositysubstantially. After addition of water, the temperature is slowly raisedto 40° C. and stirring is continued at 40° C. for about 16 hours. Afterfiltration of the suspension crystal Form D is obtained which ischaracterized by the x-ray diffraction pattern as shown in FIG. 5.

[0047] In the above example it is also possible to start from theamorphous form of Atorvastatin calcium instead of Form X.

EXAMPLE 7 Preparation of Polymorphic Form E

[0048] 60 mg of Atorvastatin Form X are dissolved in 2.0 ml 2-butanone(e.g. Fluka No. 04380) and then 2.0 ml of heptane (e.g. Fluka No. 51745)are added at ambient temperature. This mixture is heated to 50° C. for afew minutes until all solid residues are dissolved. The mixture is thenslowly cooled to 5° C. and later equilibrated at ambient temperature. Atambient temperature the solvent is slowly evaporated within about 10 to20 hours. After complete evaporation of the solvent Atorvastatin Form Eis obtained as a solid residue. The X-ray diffraction pattern of Form Eis shown in FIG. 7.

EXAMPLE 8

[0049]

[0050] a) Preparation of Atorvastatin Lactone III:

[0051] Diol acid I (5 g, 8.9 mmol) is dissolved in 10.7 ml ethanol and5.6 ml 1.6 M NH₃ in ethanol ist added at room temperature. The solutionis being stirred over 15 to 30 minutes and the solvent is subsequentlyremoved under reduced pressure to give a colorless or slightly beigefoam (5.15 g, approximately 100% yield).

[0052] Ammonium salt II (23.91 g, 41.7 mmol) is dissolved in 115 mlacetic acid. The yellow solution is being stirred at 35° C. forapproximately 16 h. 200 ml dioxane are added twice and the mixture isbeing concentrated at 40° C. and 35 mbar pressure, respectively. Theresidue is dissolved in 200 ml TBME and being washing with water andbrine and dried over magnesium sulfate. Removal of the solvent affords21.4 g (approx. 95% yield) Atorvastatin lacton III.

[0053] b) Preparation of Atorvastatin Calcium Form A Starting fromAtorvastatin Lactone III:

[0054] Lacton III (20.6 g, 38.2 mmol) is dissolved in 757 ml2-propanol/water (19:1) and 1.41 g (0.5 eq) calcium hydroxide is added.The turbid solution is stirred at 40° C. for 3 d whereupon the solutionturns into a thick suspension. White crystalls of form A are collectedby filtration and being dried at 70° C. and 20 mbar pressure overnight.Yield: 19.0 g, 86%.

EXAMPLE 9 Preparation of Atorvastatin Calcium Form A Starting fromAtorvastatin Ammonium Salt II

[0055] Ammonium salt II (2 g, 3.5 mmol) is dissolved in 20 mlTBME/isopropanol (1:2) and a solution of calciumacetat hydrate (0.5 eq)is added dropwise at room temperature. The precipitated calcium salt iscollected by filtration and dried at 70° C. and 20 mbar. (Yield 1.6 g,approx. 80%.) The obtained powder is subsequently being stirred in 58 ml2-propanol/water (19:1) at 40° C. and seeded with 5% crystalls of formA. After 4 d Atorvastatin Calcium form A can be collected by filtration(yield 1.5 g, 91%).

BRIEF DESCRIPTION OF THE DRAWINGS

[0056]FIG. 1 is a characteristic X-ray powder diffraction pattern forForm X.

[0057]FIG. 2 is a characteristic X-ray powder diffraction pattern forForm A.

[0058]FIG. 3 are characteristic X-ray powder diffraction patterns forForm B1 and B2.

[0059]FIG. 4 is a characteristic X-ray powder diffraction pattern forForm C.

[0060]FIG. 5 is a characteristic X-ray powder diffraction pattern forForm D.

[0061]FIG. 6 are characteristic Differential Scanning Calorimetry (DSC)scans of Form A and Form X.

[0062]FIG. 7 is a characteristic X-ray powder diffraction pattern forForm E.

1. (canceled)
 2. A crystalline form of[R—(R*,R*)-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt that has the X-ray powder diffraction pattern withcharacteristic peaks expressed in d-values (Å) at 31.0 (vw), 18.6 (m),17.0 (w), 15.3 (vw), 12.8 (w), 11.2 (m), 9.6 (s), 9.3 (w), 8.6 (w), 7.4(m), 6.5 (vw), 6.2 (vw), 5.47 (w), 5.21 (m), 4.64 (vs), 4.46 (s), 4.14(m), 3.97 (m), 3.74 (m), 3.62 (vw), 3.38 (w), 3.10 (m); wherein(vs)=very strong intensity; (s)=strong intensity; (m)=medium intensity;(w)=weak intensity; (vw)=very weak intensity. 3-8. (canceled)
 9. Aprocess for the preparation of a crystalline form according to claim 2,which comprises suspending a crystalline form according to claim 1 oramorphous Atorvastatin calcium in an alcohol containing a small amountof water and treating the suspension at a temperature between 10 and 60°C. 10-14. (canceled)
 15. A process for the preparation of a crystallineform according to claim 2, which comprises treating a solution ofAtorvastatin lactone in a mixture of isopropanol and water with calciumhydroxide.
 16. A pharmaceutical composition comprising an effectiveamount of a crystalline form according to claim 2, and apharmaceutically acceptable carrier.